Clinical Trial Endpoints for Macular Diseases

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1 Clinical Trial Endpoints for Macular Diseases Developed in collaboration Learning Objective Upon completion, participants should be able to: Summarize types of biomarkers of progression and treatment response in macular diseases, with an emphasis on functional endpoints in dry age-related macular degeneration 1

2 Biomarkers of Progression and Treatment Response in Dry AMD Functional Structural (imaging) Blood (genetics, flow cytometry) Lambert NG, et al. Prog Retin Eye Res. 2016;54:64-102; Gemenetzi M, et al. Eye (Lond). 2016;30:1-14. Visual Function Biomarkers in Early-Intermediate Dry AMD for Use as Clinical Trial Endpoints 2

3 Vision Impairment in Dry AMD More Than BCVA Normal Intermediate AMD Normal Late AMD Patients with late AMD (NVAMD or foveal-involving GA) often lose central BCVA Patients with intermediate AMD with HRD also experience visual function deficits In HRD, BCVA may be normal, but other measures of visual function (low luminance visual acuity, dark adaptation, MP, and color vision) are often significantly impaired Images courtesy of Dr. Lad. Personal communication, Dr. Lad; Scilley K, et al. Ophthalmology. 2002;109: Retina Overlying HRD or GA Expresses Many CD163+ Cells in the Outer Retina Inner retina Normal control (macula) HRD / GA (macula) Normal control (periphery) HRD / GA (periphery) CD163+ Infiltrating macrophages Images courtesy of Dr. Lad (unpublished data). Lad EM, et al. Graefes Arch Clin Exp Ophthalmol. 2015;253:

4 Duke Natural History Study of Early AMD Arm 1: a pilot exploratory study Evaluated 20 patients with dry AMD (AREDS stages 2 = early and 3 = intermediate/hrd) and 10 normal age-matched controls Objective: to examine 1) the feasibility of performing the visual function tests in this population and 2) test/retest reliability at 1 month (+/- 30 days) Arm 2: longitudinal observational natural history study Evaluated 101 patients Objective: to evaluate changes in visual function in dry AMD over time With 6-, 12-, 18-, and 24-month follow-up Additional testing (dark adaptometry, MPOD, questionnaires, mobile tech, genetics) Image courtesy of Dr. Lad. Chandramohan A, et al. Retina. 2016;36: ; Cocce K, et al. Invest Ophthalmol Vis Sci. 2017;58:3765. Arm 1: Conclusion of Pilot Natural History Study This study supports the feasibility of using LLVA, MAIA, MP, and CCT in subjects with early and intermediate dry AMD The intermediate AMD group exhibited visual dysfunction on LLVA, MP, and red CCT but not on computerized contrast sensitivity testing LLVA, MP, and CCT can be used as alternative clinical trial endpoints for future proof-of-concept studies in dry AMD Images courtesy of Dr. Lad. Chandramohan A, et al. Retina. 2016;36:

5 Duke Natural History Study of Early AMD Arm 1: a pilot exploratory study Evaluated 20 patients with dry AMD (AREDS stages 2 = early and 3 = intermediate/hrd) and 10 normal age-matched controls Objective: to examine 1) the feasibility of performing the visual function tests in this population and 2) test/retest reliability at 1 month (+/- 30 days) Arm 2: longitudinal observational natural history study Evaluated 101 patients Objective: to evaluate changes in visual function in dry AMD over time With 6-, 12-, 18-, and 24-month follow-up Additional testing (dark adaptometry, MPOD, questionnaires, mobile tech, genetics) Image courtesy of Dr. Lad. Chandramohan A, et al. Retina. 2016;36: ; Cocce K, et al. Invest Ophthalmol Vis Sci. 2017;58:3765. Arm 2: Data Collected Baseline Visit Follow-Up Visits Collected all listed data except blood sample Demographics Ocular, medical, and social history BCVA MAIA mesopic MP Dark adaptation (AdaptDx, MacuLogix) LLVA (standard and computerized) Cone Contrast Test Stereo color fundus photographs SD-OCT FAF and MPOD IR reflectance Quality of life questionnaire (NEI VFQ) LLQ Mobile Technology Arm (mvt) DNA blood sample for genetic testing Cocce K, et al. Invest Ophthalmol Vis Sci. 2017;58:

6 Results: Demographics All groups were balanced for: Age Sex Race/ethnicity Smoking history Past medical and past ocular history Hypertension Diabetes Myocardial infarction Coronary artery disease Dyslipidemia Dementia Cocce K, et al. Invest Ophthalmol Vis Sci. 2017;58:3765. Glaucoma suspect Fuchs dystrophy Dry eye Summary of Key Findings of Arm 2 at Baseline Measures that differentiate AREDS3 from normal controls: Standard LLVA Computerized BCVA and LLVA2 (0.5 cd/m 2 ) CCT red, green, and blue MP average threshold and percent reduced threshold Dark adaptation rod intercept Measures that differentiate AREDS3 from AREDS2: Computerized LLD2 MP percent reduced threshold Dark adaptation rod intercept Cocce K, et al. Invest Ophthalmol Vis Sci. 2017;58:3765. Sensitivity, log units Minutes 6

7 Summary of Key Findings of Arm 2 Measures that differentiate AREDS2 from normal controls: Computerized BCVA (MPOD: Observed no differences between groups with radii: 0.25, 0.5, 1, 1.75 ) Correlations: Across CCT measures: red, blue, and green Between CCT measures + LLVA2 MPOD Courtesy of Dr. Lad (unpublished data); Cocce K, et al. Invest Ophthalmol Vis Sci. 2017;58:3765. Association of LLQ With Functional Measures Participants with intermediate AMD had significantly lower LLQ composite scores than those with early AMD or controls (P <.05) Average LLQ Composite Scores Controls Early AMD Intermediate AMD LLQ composite scores were associated with computerized BCVA, standard LLVA, computerized LLVA1 and LLVA2, LLD2, rod intercept, and CCT green Only computerized LLVA1 and LLVA2 and LLD1 were statistically significant after adjusting for AMD versus control status Among participants with dry AMD, LLQ composite scores were significantly associated with computerized LLVA1 and LLVA2, LLD1, and LLD2, but only computerized LLVA1 was independent of AMD severity Courtesy of Dr. Lad (unpublished data); Thompson AC, et al. Invest Ophthalmol Vis Sci. 2017;58:

8 Conclusions of Duke Natural History Study of Early AMD Development of treatments for early-intermediate dry AMD before severe disease occurs is hampered by lack of clinical trial endpoints LLVA, MAIA MP, CCT, and dark adaptation may be used as reliable functional measures of disease progression for eyes with early and intermediate AMD Once fully characterized longitudinally, these visual function measures can serve as endpoints for future clinical trials on dry AMD LLQ is a robust, patient-centered functional measure of early visual impairment in dry AMD Future directions: In flow cytometry studies, high ratio of CD163+ to CD68+ monocytes in the blood will correlate with key clinical metrics of visual dysfunction (eg, dark adaptation, MP, LLVA) and structural markers of progression (RPD, hyperreflective foci) Sensitivity, log units Minutes Courtesy of Dr. Lad (unpublished data); Cocce K, et al. Invest Ophthalmol Vis Sci. 2017;58:3765. Correlation Between Structure and Function in Early-Intermediate AMD 8

9 Correlation Between Structure (SD-OCT) and Function (Dark Adaptation and HVF) Worse cone-mediated sensitivity and slower dark adaptation were related to structural markers on SD- OCT (greater RPE abnormal thinning) Courtesy of Dr. Lad (unpublished data); Sevilla MB, et al. Am J Ophthalmol. 2016;165: AMD Genotype and Phenotype Study (NEI, Beckman Foundation): SD-OCT Volume vs MP Retinal sensitivities at individual MP loci inversely correlate with underlying SD-OCT drusen volume Courtesy of Dr. Lad (unpublished data); Tai V, et al. Invest Ophthalmol Vis Sci. 2015;58:

10 Correlation Between Structure and Function in Type 2 Idiopathic MacTel Methods: Study Participants and Imaging MAIA-1 MP sensitivity maps were obtained during both screening and baseline visits in the international, multicenter, randomized, phase 2 trial of CNTF for type 2 MacTel (NTMT02) High-resolution SD-OCT volume scans (97 B-scans, 20 degree 20 degree, resolution 1024 A- scans per B-scan, ART 9) were acquired at the screening visit using a Spectralis unit Courtesy of Dr. Lad (unpublished data); Mukherjee D, et al. Invest Ophthalmol Vis Sci. 2017;58:BIO

11 En Face OCT Image and Corresponding B-Scans Semi-automatic segmentation of OCT layers EZ defect EZ defect Courtesy of Dr. Lad (unpublished data); Mukherjee D, et al. Invest Ophthalmol Vis Sci. 2017;58:BIO Examples of SD-OCT-MP Overlays Courtesy of Dr. Lad (unpublished data); Mukherjee D, et al. Invest Ophthalmol Vis Sci. 2017;58:BIO

12 Conclusions A high positive correlation (Pearson correlation coefficient = and for screening and baseline, respectively) was found between aggregate sensitivity loss and EZ defect area Differences in retinal sensitivity loss between affected and unaffected areas were statistically significant This software allowed determination of functional and structural changes and demonstrates that functional loss on the MP may be a surrogate marker and early predictor of EZ loss on SD-OCT in type 2 MacTel Aggregate Retinal Sensitivity Loss, db Correlation Between EZ Break Area and Aggregate Retinal Sensitivity Loss: ,000 16,000 24,000 32,000 EZ Break Area, pixels Courtesy of Dr. Lad (unpublished data); Mukherjee D, et al. Invest Ophthalmol Vis Sci. 2017;58:BIO Contact Information Call (toll-free) info@med-iq.com Please visit us online at for additional activities provided by Med-IQ. 12

13 To receive credit, click the Get Credit tab at the bottom of the Webcast for access to the evaluation, attestation, and post-test Unless otherwise indicated, photographed subjects who appear within the content of this activity or on artwork associated with this activity are models; they are not actual patients or doctors. 13

14 Abbreviations and Acronyms: Clinical Trial Endpoints for Macular Diseases AMD = age-related macular degeneration AREDS = Age-Related Eye Disease Study ART = automatic real tracking BCVA = best-corrected visual acuity CCT = cone-specific contrast CNTF = ciliary neurotrophic factor EZ = ellipsoid zone FAF = fundus autofluorescence GA = geographic atrophy HRD = high-risk drusen HVF = Humphrey visual field IR = infrared LLD = low-luminance deficit LLQ = Low Luminance Questionnaire LLVA = low-luminance visual acuity MacTel = macular telangiectasia MAIA = macular analyzer integrity assessment MP = microperimetry MPOD = macular pigment optical density NEI VFQ = National Eye Institute Visual Function Questionnaire NVAMD = neovascular age-related macular degeneration RPD = reticular pseudodrusen RPE = retinal pigment epithelium SD-OCT = spectral-domain optical coherence tomography